Role of Thymidylate Synthase Gene Variations in Colorectal Cancer Patients

  • Georg Lurje
  • Heinz-Josef Lenz
Part of the Cancer Drug Discovery and Development™ book series (CDD&D)

Summary

Colorectal cancer (CRC) is the third most common cause of cancer-related death in women and men in the United States. The current therapeutic options for patients with metastatic CRC (mCRC) are 5-fluorouracil (5-FU) based chemotherapy regimens with the addition of irinotecan (CPT-11) or oxaliplatin. It still remains a challenge for oncologists to evaluate the reasons for a wide variation in response and toxicity among patients undergoing systemic 5-FU based chemotherapy. Pharmacogenomics has emerged as a useful tool to address the variations by evaluating the interplay between genotype and drug efficacy. Identifying a reliable panel of prognostic and predictive markers is critical in selecting an individualized chemotherapy regimen based on a particular tumor genotype.

A substantial body of evidence has been accumulated in recent years, demonstrating that the level of thymidylate synthase (TS) mRNA and protein expression significantly correlates with sensitivity and resistance to TS-targeted 5-FU based chemotherapy regimens. However, the cause of the variability in TS expression still remains unclear, even though several molecular mechanisms have been identified that seem to regulate the expression of TS, which may have an impact on the response to 5-FU based chemotherapy.

TS gene expression is associated with the presence of polymorphic tandem repeats (double or triple) in the 5′-UTR region (thymidylate synthase enhancer region, TSER) of the TS gene (1,2). Patients with colon cancer who are homozygous for the triple tandem repeat (TSER-3R/3R) had significantly higher levels of intratumoral TS compared with those with double tandem repeats (3). Furthermore, Mandola et al. identified a G to C single nucleotide polymorphism (SNP) within the second repeat of the 5′-UTR TSER, which may be responsible for the transcriptional up-regulation of TS. A third polymorphic change has been reported in the 3′UTR region of TS at position 1494, a 6 bp repeat.

These three different polymorphisms in the same gene obviously complicate efforts aimed at understanding the effects of each individual polymorphism. TS expression levels, tumor response, and toxicity are functions of multiple TS gene alterations, rather than the result of one single polymorphism. This review will provide an update of the most recent data on 5-FU metabolism and TS gene variations in CRC.

Key Words

Thymidylate synthase pharmacogenomics polymorphism chemo-therapy TSER SNP TS 1494–6 bp/–6 bp 

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Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Georg Lurje
    • 1
  • Heinz-Josef Lenz
    • 1
  1. 1.Division of Medical OncologyUniversity of Southern California Norris Comprehensive Cancer Center Keck School of MedicineLos AngelesUSA

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